The goal of the Virology Program Project is to achieve an understanding of the molecular processes which characterize latent and reactivated herpesvirus infections and their contribution to pathogenesis. The project unites studies of the fundamental biochemical properties of viral genes with others that develop models for oncogenesis and immunopathology. Dr. Jack Griffith's Project will characterize HSV inter-strand exchange as a step in replication and recombination using electron microscopy and biochemical studies. He will also visualize how multi-component transcription complexes connect cis elements in promoters. Characterization of the EBV origin of lytic replication (ori-Lyt) is the focus of Dr. Shannon Kenney's Project, The Z transactivator, in addition to having a pivotal regulatory function, also may serve as the origin-binding protein for lytic replication. She will determine the contribution of cis and transacting elements to replication function and transcriptional activity. Dr. Stephen Bachenheimer will characterize athe cellular factors in transcription complexes that are activated by HSV infection and determine their role in viral regulation and potential neurovirulence. Dr. Joseph S Pagano's Project is based on the discovery of a novel EBV transdominant repressor ("RAZ") which negatively regulates expression of EBV early genes. The RAZ protein is formed by alternate splicing of the Z and R mRNAs predicted to form a chimeric protein containing domains from both Z and R. The studies will analyze RAZ function at the molecular level and clarify how RAZ participates in infection. Dr. Eng-Shang Huang will analyze HCMV infection of monocytes as a potential mechanism for viral dissemination and will determine how HCMV interferes with monocyte function. These studies will develop an in vitro model of the role of monocyte activation on the outcome of viral infection. Dr. Nancy Raab- Traub continues the development of transgenic mouse models to characterize EBV oncogenesis. Transgenic mice are a suitable means whereby the effects of expression of EBV genes can be analyzed in vivo. The ability to produce animals through cross-breeding with multiple viral genes expressed in specific cell types should identify the genes that contribute to EBV- induced oncogenesis. The VPP during the past seventeen years has stimulated a highly interactive complementary program of research on the herpesviruses and has provided significant new information that has greatly increased general understanding of herpesvirus infection and disease processes. The studies now to be addressed by the VPP continue to build with increasing molecular detail on important findings discovered in the previous funding period.